Anti-cancer therapeutic strategies based on HGF/MET, EpCAM, and tumor-stromal cross talk

Abstract

As an intelligent disease, tumors apply several pathways to evade the immune system. It can use alternative routes to bypass intracellular signaling pathways, such as nuclear factor-κB (NF-κB), Wnt, and mitogen-activated protein (MAP)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). Therefore, these mechanisms lead to therapeutic resistance in cancer. Also, these pathways play important roles in the proliferation, survival, migration, and invasion of cells. In most cancers, these signaling pathways are overactivated, caused by mutation, overexpression, etc. Since numerous molecules share these signaling pathways, the identification of key molecules is crucial to achieve favorable consequences in cancer therapy. One of the key molecules is the mesenchymal-epithelial transition factor (MET; c-Met) and its ligand hepatocyte growth factor (HGF). Another molecule is the epithelial cell adhesion molecule (EpCAM), which its binding is hemophilic. Although both of them are involved in many physiologic processes (especially in embryonic stages), in some cancers, they are overexpressed on epithelial cells. Since they share intracellular pathways, targeting them simultaneously may inhibit substitute pathways that tumor uses to evade the immune system and resistant to therapeutic agents.

Keywords: EpCAM; HGF/MET; MAP/PI3K/mTOR; NF-κB; Wnt.

Fig. 1

Controversial roles of HGF/c-Met in the immune system: (1) chemoattraction of neutrophils to tumor site; (2) activated Dc presenting TAA, boost TCD4+ regulatory cells, and anti-tumoral immune response decreased; and (3) TCD8+ activation, which led to anti-tumoral immune response

Fig. 2

C-Met can activate NF-κB in some cancer cells. By the way, indirect interactions can be assumed from experimental data. C-Met can activate STAT3 and PI3K/Akt, which are upstream and activators of NF-κB

Fig. 3

Cross talk between EpCAM, c-Met, and Wnt-β-catenin signaling pathways. Full-length EpCAM is cleaved, releasing EpCAM’s ectodomain (EpEX). Following the cleavage step, EpCAM’s cytoplasmic tail (EpICD) is released and associates with FHL-2 and β-catenin and translocates to the nucleus, upregulating transcription of EpCAM target genes via LEF consensus sites. C-Met activates MAP kinase (RAF/MEK/ERK) and PI3K/Akt signaling to induce cell proliferation and survival in cancer cells. C-Met and Wnt-β-catenin signaling pathways mainly cooperate in regulating EMT. C-Met contributes to nuclear translocation of β-catenin by its tyrosine phosphorylation or inhibition of the β-catenin degradation complex by Akt that phosphorylates glycogen synthase kinase-3β (GSK3β). This might, in turn, result in increased availability of non-bound β-catenin that may be stabilized by association with EpICD